Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential

J Med Chem. 2010 Sep 9;53(17):6386-97. doi: 10.1021/jm100697g.

Abstract

The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Benzeneacetamides / chemical synthesis*
  • Benzeneacetamides / pharmacokinetics
  • Benzeneacetamides / pharmacology
  • Benzoxazines / chemical synthesis*
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / pharmacology
  • Brain / metabolism
  • Calcium / metabolism
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Female
  • Hepatocytes / metabolism
  • Humans
  • In Vitro Techniques
  • Male
  • Maze Learning / drug effects
  • Memory, Short-Term / drug effects
  • Mice
  • Nootropic Agents / chemical synthesis*
  • Nootropic Agents / pharmacokinetics
  • Nootropic Agents / pharmacology
  • Oxazines / chemical synthesis*
  • Oxazines / pharmacokinetics
  • Oxazines / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M1 / agonists*
  • Structure-Activity Relationship

Substances

  • Benzeneacetamides
  • Benzoxazines
  • N-(1-(3-(3-oxo-2,3-dihydrobenzo(1,4)oxazin-4-yl)propyl)piperidin-4-yl)-2-phenylacetamide
  • Nootropic Agents
  • Oxazines
  • Piperidines
  • Receptor, Muscarinic M1
  • Calcium